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Protein Chemistry

🌍 Why Study Proteins?

Proteins are not just chains of amino acids—they are functional 3D machines.

  • They act as enzymes, signal transducers, transporters, and structural scaffolds (e.g. antibodies).
  • A single scaffold can support many functions → structure–function relationship is key.
  • Understanding proteins enables:
    • Drug design 💊
    • Enzyme engineering 🧪
    • Sustainable technologies 🌱

Why proteins are hard:

  • DNA has 4 building blocks → proteins have 20 amino acids
  • Even a 37-residue protein has ~10⁴⁸ possible sequences
  • Proteins are 3D, not linear → chemistry + physics + geometry

🧱 Amino Acids: The Building Blocks

General Structure

All amino acids share:

  • Cα (alpha carbon)
  • Amino group (–NH₃⁺)
  • Carboxyl group (–COO⁻)
  • Hydrogen
  • Side chain (R group) → determines properties

They are zwitterions (carry both + and − charges at physiological pH).

⚡ Amino Acids and pH: Protonation States

pH-Dependent Charges

  • Low pH (acidic): fully protonated → net positive
  • Physiological pH (~7.4): zwitterionic → net 0
  • High pH (basic): deprotonated → net negative

This applies before considering side chains.

🔑 Key idea: Charge is not fixed—it depends on pH relative to pKa.

⚖️ pKa and Isoelectric Point (pI)

  • pKa: pH at which a group is 50% protonated
  • pI: pH where the amino acid has net charge = 0

Side chains with ionizable groups shift the pI dramatically (e.g. Asp vs Lys).

🧬 Chirality and Stereochemistry

  • Most amino acids are chiral → L and D forms
  • Biological proteins use only L-amino acids
  • Exception:
    • Glycine → achiral (side chain = H)
  • Extra chiral centers:
    • Isoleucine
    • Threonine

Why life chose L-amino acids is still unknown.

🧪 Naming Side-Chain Atoms

Starting from Cα:

  • β, γ, δ, ε … (moving outward)
  • Important for:
    • Structural biology
    • Enzyme mechanisms
    • Mutational analysis

🧊 Classification of Amino Acids

1️⃣ Nonpolar (Hydrophobic)

  • Glycine, Alanine, Valine, Leucine, Isoleucine
  • Side chains = hydrocarbons
  • Avoid water → buried inside proteins

🔹 Reactivity: very low 🔹 Function: structural packing, hydrophobic cores

2️⃣ Aromatic Amino Acids

  • Phenylalanine (Phe)
  • Tyrosine (Tyr)
  • Tryptophan (Trp)

📡 Spectroscopy relevance

  • Trp absorbs strongly at 280 nm → used to measure protein concentration
  • Tyr absorbs moderately
  • Phe weakly absorbs UV

🔹 Reactivity:

  • Phe: low
  • Tyr: moderate (–OH can be modified)
  • Trp: chemically sensitive, fluorescence reporter

3️⃣ Proline – The Structural Disruptor

  • Side chain forms a ring with backbone
  • Technically an imino acid
  • Severely restricts backbone flexibility

🔹 Reactivity: low 🔹 Structural role: breaks α-helices, induces turns

4️⃣ Basic (Positively Charged) Amino Acids

  • Lysine (Lys) → + charged at physiological pH
  • Arginine (Arg) → always + charged
  • Histidine (His) → pKa ≈ 6 → can switch charge state

🔹 Reactivity:

  • Lys: reactive (modifications, cross-linking)
  • Arg: strong electrostatics, less chemically reactive
  • His: highly reactive → acid/base catalysis

🧠 Histidine is special: perfect for enzyme active sites

5️⃣ Acidic (Negatively Charged) Amino Acids

  • Aspartate (Asp)
  • Glutamate (Glu)

🔹 Charge: −1 at physiological pH 🔹 Reactivity: moderate 🔹 Roles: catalysis, salt bridges, metal binding

6️⃣ Polar Uncharged (Hydroxyl-Containing)

  • Serine (Ser)
  • Threonine (Thr)
  • Tyrosine (Tyr)

🔹 Reactive residues

  • –OH group enables:
    • Phosphorylation
    • Hydrogen bonding
    • Nucleophilic catalysis (Ser!)

7️⃣ Amide Side Chains (Polar, Non-Reactive)

  • Asparagine (Asn)
  • Glutamine (Gln)

🔹 Charge: neutral 🔹 Reactivity: low

  • Amide group is resonance-stabilized
  • Excellent for hydrogen bonding
  • Structural, not catalytic

8️⃣ Sulfur-Containing Amino Acids

Methionine (Met)

  • Hydrophobic
  • Initiates protein synthesis
  • Sulfur is chemically inert

Cysteine (Cys)

  • Contains thiol (–SH)
  • Can form disulfide bonds
  • Highly reactive

🔥 Most reactive amino acid

  • Redox chemistry
  • Catalysis
  • Structural stabilization

🧠 Reactive vs Non-Reactive Amino Acids (Big Picture)

Highly Reactive

  • Cysteine → redox, disulfides
  • Histidine → acid/base catalysis
  • Serine → nucleophile
  • Tyrosine → phosphorylation

Moderately Reactive

  • Aspartate, Glutamate
  • Lysine

Largely Non-Reactive

  • Glycine, Alanine, Valine, Leucine, Isoleucine
  • Asparagine, Glutamine
  • Methionine
  • Phenylalanine

🔑 Rule of thumb: Reactivity comes from ionizable or nucleophilic side chains, not size.

🎯 Core Takeaways

  • Amino acids are zwitterionic, chiral, and pH-dependent
  • Side chains determine:
    • Charge
    • Reactivity
    • Structure
    • Function
  • Only a subset of amino acids drive catalysis
  • Protein chemistry = controlled diversity

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